Natural killer (NK) cells are lymphocytes that destroy abnormal cells (virus infected or malignant cells) through the release of cytolytic granules or immune stimulatory cytokines. NK cells express both activating and inhibitory receptors on their cell surface. It is believed that a balance of signaling from both activating and inhibitory receptors regulates the NK cell. The mechanism by which NK cells develop their repertoire of receptors is now beginning to be understood. Our laboratory has recently demonstrated that the interaction of inhibitory Ly49 receptors on NK cells with their MHC class I ligands early in development is responsible for functional maturation of NK cells (termed "licensing"). This event likely takes place as the NK cell matures in the bone marrow. In the absence of "licensing", the NK cell fails to carry out a robust.immune responses upon stimulation by a target cell. On the other hand, little is known about the role of activating receptors in NK cell development. The Ly49H receptor is an activating receptor, expressed on the surface of NK cells in certain strains of mice, which confers resistance to murine cytomegalovirus (MCMV) infection. Recently, the ligand for this receptor has been identified as the MCMV-encoded protein m157. The core hypothesis is that the constitutive expression of m157 will alter the development and/or function of Ly49H+ NK cells. The goal of this proposal is to test this hypothesis via three specific aims. The studies in Aim 1 will determine if the expression of m157, a viral-encoded protein, will alter the development of NK cells in the absence of Ly49H. This will be accomplished by generating an m157-expressing transgenic mouse in a strain that does not express the Ly49H receptor. The studies in Aim2 will determine if expression of m157 in the presence of Ly49H will alter NK cell development. This will be accomplished by mating the mouse generated in Aim 1 with a strain of mouse that expresses Ly49H. The studies in Aim 3 will determine if the expression of m157 outside of the bone marrow alters NK cell development and/or function by expressing ml 57 in a liver-specific or intestine-specific fashion. Natural killer (NK) cells play an important role in the immune response to viruses and tumors. Insight into the development of NK cells could result in the generation of novel NK cell-based therapies that may prove useful in the treatment of viral infection and cancers.